A
long-standing
goal
of
evolutionary
biology
is
to
decode
how
changes
in
gene
regulatory
networks
contribute
human-specific
traits.
Human
accelerated
regions
(HARs)
are
prime
candidates
for
driving
modifications
human
development.
The
PLoS Computational Biology,
Год журнала:
2024,
Номер
20(1), С. e1011802 - e1011802
Опубликована: Янв. 16, 2024
The
effects
of
transcription
factor
binding
sites
(TFBSs)
on
the
activity
a
cis-regulatory
element
(CRE)
depend
local
sequence
context.
In
rod
photoreceptors,
for
(TF)
Cone-rod
homeobox
(CRX)
occur
in
both
enhancers
and
silencers,
but
context
that
determines
whether
CRX
contribute
to
activation
or
repression
is
not
understood.
To
investigate
context-dependent
sites,
we
fit
neural
network-based
models
activities
synthetic
CREs
composed
photoreceptor
TFBSs.
revealed
consistently
make
positive,
independent
contributions
CRE
activity,
while
negative
homotypic
interactions
between
cause
multiple
function
as
silencers.
can
be
overcome
by
presence
other
TFBSs
either
interact
cooperatively
with
positive
activity.
thus
determined
balance
heterotypic
interactions,
TFBSs,
interactions.
Our
findings
explain
observed
patterns
among
genomic
CRX-bound
suggest
may
require
diverse
Journal of Virology,
Год журнала:
2024,
Номер
98(6)
Опубликована: Май 2, 2024
ABSTRACT
Kaposi’s
sarcoma-associated
herpesvirus
(KSHV)
belongs
to
the
gamma-herpesvirus
family
and
is
a
well-known
human
oncogenic
virus.
In
infected
cells,
viral
genome
of
165
kbp
circular
DNA
wrapped
in
chromatin.
The
tight
control
gene
expression
critical
for
latency,
transition
into
lytic
phase,
development
viral-associated
malignancies.
Distal
cis
-regulatory
elements,
such
as
enhancers
silencers,
can
regulate
position-
orientation-independent
manner.
Open
chromatin
another
characteristic
feature
enhancers.
To
systematically
search
enhancers,
we
cloned
all
open
regions
KSHV
downstream
luciferase
tested
their
enhancer
activity
uninfected
cells.
A
silencer
was
detected
upstream
latency-associated
nuclear
antigen
promoter.
Two
constitutive
were
identified
K12p-OriLyt-R
ORF29
Intron
regions,
where
tissue-specific
enhancer.
following
promoters:
OriLyt-L,
PANp,
ALTp,
terminal
repeats
(TRs)
acted
lytically
induced
replication
transcription
activator
(RTA),
master
regulator
cycle,
sufficient
induce
We
propose
that
TRs
span
about
24
region
serve
“viral
super-enhancer”
integrates
repressive
effect
(LANA)
with
activating
RTA.
Utilizing
CRISPR
activation
interference
techniques,
determined
connections
between
these
regulated
genes.
described
here
provide
an
additional
layer
complex
regulation
herpesviruses.
IMPORTANCE
this
study,
performed
systematic
functional
assay
identify
elements
within
herpesvirus,
(KSHV).
Similar
other
herpesviruses,
presents
both
latent
phases.
Therefore,
our
assays
during
infection,
under
conditions.
two
one
which
seems
be
addition,
four
are
responsive
identified.
Furthermore,
major
latency
promoter
locus.
repeats,
spanning
kbp,
seem
like
RTA
transition.
Cancer Cell International,
Год журнала:
2025,
Номер
25(1)
Опубликована: Янв. 7, 2025
Super-enhancers
(SEs)
represent
a
distinct
category
of
cis-regulatory
elements
notable
for
their
robust
transcriptional
activation
capabilities.
In
tumor
cells,
SEs
intricately
regulate
the
expression
oncogenes
and
pivotal
cancer-associated
signaling
pathways,
offering
significant
potential
cancer
treatment.
However,
few
studies
have
systematically
discussed
crucial
role
in
hepatocellular
carcinoma
(HCC),
which
is
one
most
common
liver
cancers
with
late-stage
diagnosis
limited
treatment
methods
advanced
disease.
Herein,
we
first
summarize
identification
intricate
processes
formation
organization
super-enhancers.
Subsequently,
delve
into
roles
molecular
mechanisms
within
framework
HCC.
Finally,
discuss
inhibitors
targeting
key
SE-components
effects
on
conclusion,
this
review
meticulously
encapsulates
distinctive
characteristics
underscores
context
carcinoma,
presenting
novel
perspective
super-enhancers
as
emerging
therapeutic
targets
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Янв. 16, 2025
Silencers,
the
yin
to
enhancers'
yang,
play
a
pivotal
role
in
fine-tuning
gene
expression
throughout
genome.
However,
despite
their
recognized
importance,
comprehensive
identification
of
these
regulatory
elements
genome
is
still
its
early
stages.
We
developed
method
called
Ss-STARR-seq
directly
determine
activity
silencers
whole
In
this
study,
we
applied
human
cell
lines
K562,
LNCaP,
and
293
T,
identified
134,171,
137,753,
125,307
on
genome-wide
scale,
respectively,
function
various
cells
cell-specific
manner.
Silencers
exhibited
substantial
enrichment
transcriptional-inhibitory
motifs,
including
REST,
demonstrated
overlap
with
binding
sites
repressor
transcription
factors
within
endogenous
environment.
Interestingly,
H3K27me3
did
not
reflect
silencer
but
facilitated
silencer's
inhibitory
expression.
Additionally,
have
any
significant
histone
markers
at
level.
Our
findings
unveil
that
aspect-silencers
only
transition
into
enhancers
diverse
also
achieve
functional
conversion
insulators.
Regarding
biological
effects,
knockout
experiments
underscored
redundancy
specificity
regulating
proliferation.
summary,
study
pioneers
elucidation
landscape
cells,
delineates
global
features,
identifies
specific
influencing
cancer
critical
regulation.
Here,
authors
technique
identify
tens
thousands
cells.
These
possess
unique
epigenetic
features
are
capable
cellular
phenotypes.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Фев. 5, 2025
The
role
of
non-coding
regulatory
elements
and
how
they
might
contribute
to
tissue
type
specificity
disease
phenotypes
is
poorly
understood.
Autosomal
Dominant
Leukodystrophy
(ADLD)
a
fatal,
adult-onset,
neurological
disorder
that
characterized
by
extensive
CNS
demyelination.
Most
cases
ADLD
are
caused
tandem
genomic
duplications
involving
the
lamin
B1
gene
(LMNB1)
while
small
subset
deletions
upstream
gene.
Utilizing
data
from
recently
identified
families
carry
LMNB1
but
do
not
exhibit
demyelination,
patient
tissues,
CRISPR
edited
cell
lines
mouse
models,
we
have
silencer
element
lost
in
patients
specifically
targets
expression
oligodendrocytes.
This
consists
CTCF
binding
sites
mediate
three-dimensional
chromatin
looping
recruitment
PRC2
transcriptional
repressor
complex.
Loss
identifies
for
causation.
An
oligodendrocyte-specific
determines
fatal
widely
expressed
nuclear
protein
(Lamin
B1)
suggests
ACS Omega,
Год журнала:
2023,
Номер
8(33), С. 30315 - 30329
Опубликована: Авг. 7, 2023
Research
on
the
interactions
of
naturally
existing
flavonoids
with
various
noncanonical
DNA
such
as
i-motif
(IM)
structures
is
helpful
in
comprehending
molecular
basis
binding
mode
well
providing
future
direction
for
application
and
invention
novel
effective
therapeutic
drugs.
IM
have
been
identified
prospective
anticancer
targets,
are
smaller
molecules
a
variety
health-promoting
attributes,
including
activities.
The
extensive
investigation
comprising
series
techniques
reveals
contrasting
behavior
fisetin
morin
structures.
We
discovered
that
structural
alterations
hydroxyl
groups
located
at
different
places
aromatic
rings
influence
flavonoid's
reactivity.
This
minor
alteration
appears
to
be
critical
morin's
capacity
interact
differentially
HRAS1
HRAS2
DNA.
Hence,
an
efficient
ligand
considered
exploration
opens
up
possibility
employing
strategy
regulation
gene
expression
cancerous
cells.
Our
finding
also
flavonoid-mediated
specific
interaction
while
pointing
toward
tangible
strategies
drug
discovery
other
essential
cellular
functions.
Briefings in Bioinformatics,
Год журнала:
2023,
Номер
24(5)
Опубликована: Авг. 15, 2023
Silencers
are
noncoding
DNA
sequence
fragments
located
on
the
genome
that
suppress
gene
expression.
The
variation
of
silencers
in
specific
cells
is
closely
related
to
expression
and
cancer
development.
Computational
approaches
exclusively
rely
information
for
silencer
identification
fail
account
cell
specificity
silencers,
resulting
diminished
accuracy.
Despite
discovery
several
transcription
factors
epigenetic
modifications
associated
with
genome,
there
still
no
definitive
biological
signal
or
combination
thereof
fully
characterize
posing
challenges
selecting
suitable
signals
their
identification.
Therefore,
we
propose
a
sophisticated
deep
learning
framework
called
DeepICSH,
which
based
multiple
data
sources.
Specifically,
DeepICSH
leverages
convolutional
neural
network
automatically
capture
biologically
relevant
combinations
strongly
originating
from
diverse
array
signals.
Furthermore,
utilization
attention
mechanisms
facilitates
scoring
visualization
these
combinations,
whereas
employment
skip
connections
fusion
multilevel
features
thereby
empowering
accurate
within
cells.
Extensive
experiments
HepG2
K562
line
sets
demonstrate
outperforms
state-of-the-art
methods
Notably,
introduce
first
time
multi-omics
classifying
strong
weak
achieving
favorable
performance.
In
conclusion,
shows
great
promise
advancing
study
analysis
complex
diseases.
source
code
available
at
https://github.com/lyli1013/DeepICSH.
Nature Biomedical Engineering,
Год журнала:
2024,
Номер
8(7), С. 890 - 908
Опубликована: Май 22, 2024
Abstract
The
functions
of
non-coding
regulatory
elements
(NCREs),
which
constitute
a
major
fraction
the
human
genome,
have
not
been
systematically
studied.
Here
we
report
method
involving
libraries
paired
single-guide
RNAs
targeting
both
ends
an
NCRE
as
screening
system
for
Cas9-mediated
deletion
thousands
NCREs
genome-wide
to
study
their
in
distinct
biological
contexts.
By
using
K562
and
293T
cell
lines
embryonic
stem
cells,
show
that
can
redundant
functions,
many
ultra-conserved
silencer
activity
play
essential
roles
growth
cellular
responses
drugs
(notably,
element
PAX6_Tarzan
may
be
critical
heart
development,
removing
it
from
cells
led
defects
cardiomyocyte
differentiation).
high-throughput
screen,
is
compatible
with
single-cell
sequencing,
allow
identification
druggable
NCREs.